19-Hydroxy-19-methyl-6,9α-epoxymethano-PGF compounds

ABSTRACT

The present invention provides novel 19-hydroxy-19-methyl-6,9α-epoxy-methano-PGF compounds which are useful for pharmacological purposes, e.g., anti-asthmatic indications.

CROSS REFERENCE TO RELATED APPLICATION

The present invention is a divisional application of U.S. Ser. No. 054,720, filed 5 July 1979, now U.S. Pat. No. 4,225,507.

BACKGROUND OF THE INVENTION

The present invention provides novel prostacyclin analogs. Particularly, the present invention relates to prostacyclin analogs substituted at the C-19 position by hydroxy.

Particularly, the present invention relates to 19-hydroxy-19-methyl-6,9.sub.α -epoxymethano-PGF compounds. The novel prostacyclin analogs are useful for pharmacological purposes, e.g., as anti-asthmatic agents. The preparation and use of these compounds is incorporated here by reference from U.S. Ser. No. 054,720, filed 5 July 1979, now U.S. Pat. No. 4,225,507.

PRIOR ART

For background on prostacyclin, see for example R. A. Johnson, et al., Prostaglandins 12, 915-928 (1976) and R. A. Johnson, et al., J. Am. Chem. Soc. 100, 7690-7704 (1978), and, as to pharmacological activity, the references cited therein. For analogs of prostacyclin, see, for example, J. Fried, et al., Proc. Natl. Acad. Sci. U.S.A. 74, 2199-2203, K. C. Nicolaou, et al., J.C.S. Chem. Comm. 1977, 331-332, N. A. Nelson, J. Am. Chem. Soc. 99, 7362-7363 (1977), and K. Kojima, et al., Tetra. Letters, 1978, (1977), and K. Kojima, et al., Tetra. Letters, 1978, 3743-3746. Regarding the nomenclature for analogs of PGI₂, see R. A. Johnson, et al., Prostaglandins, 15, 737-740 (1978).

SUMMARY OF THE INVENTION

The present invention particularly provides a prostacyclin-type compound of the formula ##STR1## wherein A₂ is --CH₂ O-- with --CH₂ bonded to the cyclopentane ring and E₁ is --CH₂ --;

wherein L₁ is

(1) --(CH₂)_(n) --, wherein n is one to 5, inclusive,

(2) --(CH₂)_(p) --CF₂ --, wherein p is 2, 3, or 4; or

(3) --CH₂ --CH═CH--;

wherein M₁ is ##STR2## wherein Q is oxo, α--H:β--H, α--OH:β--R₄, or α--R₄ :β--OH, wherein R₄ is hydrogen or alkyl of one to 4 carbon atoms, inclusive;

wherein R₁ is

(1) --COOR₃,

(2) --CH₂ OH,

(3) --CH₂ N(R₇)(R₈),

(4) --CO--N(R₇)(R₈),

(5) --CO--NH--SO₂ --R₁₅, or

(6) tetrazolyl,

wherein R₃ is

(a) hydrogen,

(b) alkyl of one to 12 carbon atoms, inclusive,

(c) cycloalkyl of 3 to 10 carbon atoms, inclusive,

(d) aralkyl of 7 to 12 carbon atoms, inclusive,

(e) phenyl,

(f) phenyl substituted with one, 2, or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive;

(g) --(Ph)--CO--CH₃,

(h) --(p--Ph)--NH--CO--(p--Ph)--NH--CO--CH₃,

(i) --(p--Ph)--NH--CO--(p--Ph),

(j) --(p--Ph)--NH--CO--CH₃,

(k) --(p--Ph)--NH--CO--NH₂,

(l) --(p--Ph)--CH═N--NH--CO--NH₂,

(m) β--naphthyl,

(n) --CH₂ --CO--R₁₆,

wherein --(Ph)-- is inter-phenylene and --(p--Ph) is inter-para-phenylene or para-phenyl;

wherein R₁₆ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, or

(o) a pharmacologically acceptable cation; wherein R₇ and R₈ are hydrogen, alkyl of one to 12 carbon atoms, inclusive, benzyl, or phenyl, being the same or different, and wherein R₁₅ is hydrogen, alkyl of one to 12 carbon atoms, inclusive, phenyl, phenyl-substituted with one, 2, or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive, or phenyl substituted with hydroxycarbonyl or alkoxycarbonyl of one to 4 carbon atoms, inclusive, in the alkoxy group

wherein R₂ is hydrogen, hydroxyl, or hydroxymethyl,

wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro, and

wherein X is

(1) trans--CH═CH--,

(2) cis--CH═CH--,

(3) --C.tbd.C--, or

(4) --CH₂ CH₂ --.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention particularly relates to the following compounds:

(5Z)-2-Decarboxy-2-hydroxymethyl-9-deoxy-6,9α-epoxymethano-Δ.sup.5,19-hydroxy-19-methyl-PGF₁,

(5Z)-2-Decarboxy-2-hydroxymethyl-9-deoxy-6,9α-epoxymethano-Δ.sup.5 -16,16-difluoro-19-hydroxy-19-methyl-PGF₁,

2-Decarboxy-2-hydroxymethyl-9-deoxy-6ε,9α-epoxymethano-19-hydroxy-19-methyl-PGF₁, and

2-Decarboxy-2-hydroxymethyl-9-deoxy-6ε,9α-epoxymethano-16,16-difluoro-19-hydroxy-19-methyl-PGF₁. 

I claim:
 1. A prostacyclin-type compound of the formula ##STR3## wherein A₂ is --CH₂ O-- with --CH₂ bonded to the cyclopentane ring and E₁ is --CH₂ --;wherein L₁ is(1) --(CH₂)_(n) --, wherein n is one to 5, inclusive, (2) --(CH₂)_(p) --CF₂ --, wherein p is 2, 3, or 4; or (3) --CH₂ --CH═CH--; wherein M₁ is ##STR4## wherein Q is oxo, α--H:β--H, α--OH:β--R₄, or α--R₄ :β--OH, wherein R₄ is hydrogen or alkyl of one to 4 carbon atoms, inclusive; wherein R₁ is(1) --COOR₃, (2) --CH₂ OH, (3) --CH₂ N(R₇)(R₈), (4) --CO--N(R₇)(R₈), (5) --CO--NH--SO₂ --R₁₅, or (6) tetrazolyl, wherein R₃ is(a) hydrogen, (b) alkyl of one to 12 carbon atoms, inclusive, (c) cycloalkyl of 3 to 10 carbon atoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl, (f) phenyl substituted with one, 2, or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive; (g) --(Ph)--CO--CH₃, (h) --(p-Ph)--NH--CO--(p-Ph)--NH--CO--CH₃, (i) --(p-Ph)--NH--CO--(p-Ph), (j) --(p-Ph)--NH--CO--CH₃, (k) --(p-Ph)--NH--CO--NH₂, (l) --(p-Ph)--CH═N--NH--CO--NH₂, (m) β--naphthyl, (n) --CH₂ --CO--R₁₆, wherein --(Ph)-- is inter-phenylene and --(p-Ph) is inter-para-phenylene or para-phenyl; wherein R₁₆ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, or(o) a pharmacologically acceptable cation; wherein R₇ and R₈ are hydrogen, alkyl of one to 12 carbon atoms, inclusive, benzyl, or phenyl, being the same or different, and wherein R₁₅ is hydrogen, alkyl of one to 12 carbon atoms, inclusive, phenyl, phenyl-substituted with one, 2, or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive, or phenyl substituted with hydroxycarbonyl or alkoxycarbonyl of one to 4 carbon atoms, inclusive, in the alkoxy group wherein R₂ is hydrogen, hydroxyl, or hydroxymethyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro, and wherein X is(1) trans--CH═CH--, (2) cis--CH═CH--, (3) --C.tbd.C--, or (4 ) --CH₂ CH₂ --.
 2. A compound according to claim 1, wherein R₁ is --CH₂ OH.
 3. A compound according to claim 2, wherein M₁ is ##STR5## with bonds to A₂ and L₁ as shown.
 4. A compound according to claim 3, wherein L₁ is --(CH₂)₂ -- Q is α--OH:β--H, R₂ is hydroxyl, and X is trans--CH═CH--.
 5. A compound according to claim 2, wherein M₁ is ##STR6##
 6. A compound according to claim 5, wherein L₁ is --(CH₂)₂ --, Q is α--OH:β--H, R₂ is hydroxyl, and X is trans--CH═CH--. 